The purpose of this program is to characterize and explain age associated losses of muscle strength, its relationships to disability and physical activity, to understand the effects of age and gender on the exercise response to exercise, and to examine the phyiological contributions of motor units to strength production. 1. Analyses from the Baltimore Longitudinal Study of Aging. Over the past several years, we have begun to publish data showing genetic contributions of selected genes on muscle strength and hypertrophy. Individuals heterozygotic for a null polymorph of CNTF, a growth factor that directly affects peripheral neurons and muscle, had higher strength levels than individuals without the null polymorph particularly at faster contraction speeds. The increase in strength was associated with greater force generation per unit of muscle mass which has been called muscle quality. In addition, we found that heterozygotic subjects seem to use smaller motor units to generate higher force levels than homozygotic subjects. This suggests a more efficient use of motor units at higher force levels. IGF2 Apal polymorphism has been reported associated with obesity. We found that individuals homozygous for the IGF2 G allele do not exhibit higher body mass, BMI or fat mass compared to homozygous A allele subjects; however, Caucasians with the A/A genotype exhibit higher fat mass than G/G individuals. In addition, G/G homozygotes have greater isokinetic concentric muscle strength across the adult age span. We are also exploring other factors that may contribute to the strength loss. The levels of free testosterone (as estimated by the free testosterone index) but not total serum testosterone has an effect on muscle strength independent of muscle mass. To examine the impacts of muscle strength, we examined the association between muscle strength and all cause mortality in BLSA men. In men less than 60 years of age, an association between the rate of change in strength over time was found with mortality, with men who did not show losses in strength over many years showing greater survival. In men over 60 years of age, the actual level of strength was more important than how it was changing over time. To assess the impact of strength on daily functions, we compared timed gait to muscle strength around the knee in BLSA women and men aged 20-90. Rapid gait speed was found to increase linearly to a strength of about 200 Nm, with no further changes in speed at higher strength levels. The plateauing of the strength gait speed curve, argues that 200 Nm represents an upper threshold where an excess in physiological function accumulates that does not increase performance. What was particularly revealing was that 10-15% of men fell above this plateau level, while none of the women reached this level. Also, a plateau was found for normal gait speed where 20% of women fell on the plateau, as well as 40% of men. The striking observation is that women are dependent on the strength to gait speed linear relationship to a far greater extent than are men. Age-associated changes in strength should have a greater negative impact on women's gait than on men's gait, particularly at faster speeds. As another measure of functional ability, we have measured dynamic posturography on BLSA subjects using the same protocol now being used by NASA in testing their astronauts. The data will be compared to the astronaut data to (1) examine the implications of increasing age on potential long term space flight, and (2) document the sequence and magnitude of changes in various elements of the balance system during normal aging. In addition, we will examine the relationship between muscle strength, cardiovascular fitness, leisure time physical activity on balance performance, and the association between balance performance, gait and falls. Analysis was done to examine the sensory-motor adaptive response of 77 year old US Senator John H. Glenn, Jr. to space flight. Senator Glenn's pre-flight balance control performances were well above the median for an age-matched control group. Postural recovery dynamics revealed few differences between Senator Glenn's neuro-adaptive responses to space flight and those of a group of younger astronauts. We interpret these findings as evidence that increasing age alone does not necessarily impair balance function. A methodological issue was addressed in how to analyze data from computerized dynamic posturography. A probabilistic model was developed to deal with the occurrence of falls during the testing. A second area of interest is in interventions on muscle physiologyand health. A contract with the University of Maryland comparing the exercise response in young and old women and men is completed. Currently the data are under analysis, with multiple manuscripts published. Muscle samples from the vastus medialis were obtained from sedentary young (20-30 yr.) and older (65-75 yr.) men and women before and after a nine-week unilateral heavy resistance strength training (ST) program for the knee extensor muscle group. Publications over the past year, demonstrated that the level of muscle damage from the resistive training did not differ between young and old men with both groups showing about 6-7% damage. Large-scale gene expression patterns from approximately 4000 gene were examined using high-density cDNA microarrays and quantitative PCR. RNA was hybridized to cDNA filter microarrays and comparisons were made among arrays to determine differential gene expression. Sex had the strongest influence on muscle gene expression, with differential expression (>1.7-fold) observed for ~200 genes between men and women (~75% with higher expression in men). Age contributed to differential expression as well, as approximately 50 genes were identified as differentially expressed (>1.7-fold) in relation to age, representing structural, metabolic, and regulatory gene classes. Sixty nine genes were identified as being differentially expressed (>1.7-fold) in all groups in response to ST, and the majority of these were down-regulated. These results provide evidence for significant differences in skeletal muscle gene expression between men and women, between young and older individuals, and as a result of ST. In a separate project we used electromyostimulation as an alternative to resistive strength training and the use of a pedometer to encourage increased activity in patients with osteoarthritis of the knee. We are working to develop alternative strategies that will give individuals differing strategies to maintain and increase strength. The data are currently being analyzed. 3. Motor Unit Physiology We continue examine age associated changes in the motor unit and the impact on strength in BLSA subjects. In previous work, we had found that product of average motor unit size and firing rate accounts for more than 70% of the variance in force generation in a large sample of subjects. We have examined the relationship between motor unit size, firing rate and the surface EMG signal. The latter is frequently used to assess muscle function in kinesiology. Motor unit size is more critical than firing rate in accounting for the surface signal in the quadriceps femoris.We are currently analyzing data from the exercise intervention done with University of Maryland and find that smaller motor units are used to generate moderate force levels, post training and 6 months after completion of training when compared to baseline. The pattern suggests an efficiency of use in how motor units are implemented at moderate force levels, that should be associated with less fatigability.